Syntheses of spirilloxanthin



, sulfonic acid, preferably the former. The6-methoxy-6- 60 reaction,e.g. by treatment with bromoethylacetate, potas- 3 ,l6 fi,65 8 PatentedDec. 8, 1964 United States Patent ce The latter compound is thendehydrated with a dehydrating agent, e.g. phosphorus oxychloride andpyridine, or heat, preferably'in the presence of a trace of an acidcatalyst or iodine, to form ethyl 3,7-dimethyl-7-methoXy-2- octenoate(IV). The latter compound is treated with N- bromosuccinirnide anddehydrohalogenated by heating to form ethyl3,7-dimethyl-7-methoxy-octa-2,4-dienoate (V). This compound is thenreduced with a group I-group III mixed metal hydride, e.g. lithiumaluminum hydride, 10 to 3,7-dimethyl-7-methoXy-octa-2,4-dien-l-ol (VI).The

latter compound is reacted with triphenyl phosphorus hydrobromide' toform 3,7-dimethyl-7-methoxy-octet-2,4- S iriiloxanthin, sometimes calledrhodoviolasin, is a dien-l-yl triphenyl phosphorus bromide (VII), whichin known carotenoid [see, e.g. Karrer and Koenig, Helv. turn is reactedwith crocetin dialdehyde in the presence of Chim. Acta, 23, 460 (1940)],useful as a natural coloring an alkali metal alcoholate such as sodiummethylate to agent for feedstuifs and foodstuffs. give spirilloxanthin(VIII).

The present invention relates to two processes which The reaction schemefor the preparation is given below.

0 CH; O OH; O CH;

3,160,658 SYN'E'HESES OF SPEHLLUXANTHIN Joseph Donald Surmatis, WestCaldwell, Nl, assignor to Hoiimann-La Roche Inn, Nutley, NJ, acorporation of New Jersey 5 No Drawing. Original application May 31,1962, Ser. No. 198,719. Divided and this application Mar. 4, 1963, Ser.No. 262,305

5 Claims. (Cl. 260-543) This invention relates to methods for thesynthesis of spirilloxanthin and to novel intermediates therefor.

\i/ \l/ /CO0C1H5 9/ 00001115 0 OH l u I (I) (II) (IV) OCH; Br 0 on, 00n. CH21 (CuH5)3 //ornon 00001115 (VII) (VI) (V) 0 CH3 \l/ I l vrn havenow been discovered for its total synthesis The (2) The second method ofpreparation is as follows:

processes ofthe invention are as follows:G-methoxy-6-methyl-heptan-2-one (H) is treated with sodi- (1)6-methyl-5-hepten-2-one (I) is treated with methyl 7 um ace lide to orm3-h dro -7- th -3,7-d' alcohol and concentrated sulfuric acid 1n thecold, 1.e. at W L y Xy me (my methyl a temperature in the range of 0 to10 C. Then the Peta-Lyme latter comljound hydrogenated reaction mixture'is made alkaline, preferably with an. m the presfance alead'Panadmm'calcmm carbonate aqueous alkali metal hydroxide, e.g.sodium hydroxide, to catalyst [Lmdlan Helv- Chlm- Acta, 442, give6-methoxy-6-methyl-heptan-2-one (II). Alternativeto form 3- Y y- Ydimethylccta-l-ene ly, the reaction can be carried out by heating-methyl-S-i (X). This compound is reacted with triphenyl phoshepten-Z-one (I) with methyl alcohol and an aromatic phorus'hydrobromide to yield 7-methoXy-3,7-dimethylsulfonic acid such asp-toluenesulfonic acid, or benzene 1 triphenyl Phosphorus bromide (XI)The latter compound is reacted with crocetin dialdehyde to give1,1'-din1ethoxy-1,1',2,2-tetrahydrolycopene (XII). sium bromide, andZinc metal followed by acidification of Then the lattfir compound istreated wlth Ni the solution, with aqueous minsral id to producecinirnide and dehydrobrominated to yield sprrilloxanthm ethyl3-hydroxy-3,7-dimethyl-7-methoxyoctanoate (III). (VIII).

rnethyl-heptan-Z-one (It) is then reacted in a Reformatsky q (3 Thereaction scheme for the preparation is given below.

CH3 0 CH3 \l/ \l/ 0 OH; O CH; Br \i/ Calms.

I OH vnr The process of the invention will be better understood byreference to the following examples which are given for illustrationpurposes only and are not meant to limit the flask is cooled in an icebath until the temperature of the methyl alcohol is 10 C. or lower. Then800 ml. of con centrated sulfuric acid is slowly dropped into the methylalcohol over a period of one hour while coohng and stirring. 2 kg. of6-methyl-5-hepten-2-one (I) is added to the cool reaction mixture all atonce with vigorous stirring. The ice bath is removed and the stirringcontinued for 8 hours. The stirring is thenstopped and the reactionmixture flowed to stand at room temperature for 8 hours. The reactionmixture is poured into 10 liters of ice water and to the resultingmixture 900 ml. of aqueous sodium hydroxide solution is added. Thealkaline reaction mixture is stirred for one hour, the oil separatedoff, and the aqueous portion extracted 4 times, each time with 1 literof benzene. extracts are combined and washed until neutral with water.The benzene is removed by distillation under the vacuum of a water pump,and the residual oil fractionated; boiling point 107-109 C. at 25 mm.

An alternative process for the preparation of6-methoxy-G-methyl-heptan-Z-one (II) is as follows: In a 12'- literround-bottom flask provided ,With a stirrer, condenser, and thermometeris added 5 liters of methyl al- The oil and the benzene cohol, 2 kg. of6-methyl-5-hepten-2-one (I), and g. of V para-toluene sulfonic acid. Thesolution is stirred at reflux temperature for 24 hours. The methylalcohol is removed by distillation under the vacuum of a water pump.

The residual oil is washed two times, each time with 2 liters of water.The water washes are combined and extracted with 500 ml. of benzene. Theresidual oil is then combined with the benzene extract and the benzeneremoved by distillation with a water pump. The residual oil is thenfractionally distilled; boiling point 82-84" C. at 9 mm. mercury.

(b) Preparation of Ethyl 3-Hydr0xy-3,7- Dimethyl-7-Zllethoxyoctanoate(111) In a 2-liter round-bottom flask fitted with a stirrer, condenser,and thermometer is added 300 g. of bromoethylacetate, 15 g. of potassiumbromide, 750 ml. of benzene,

and 200 g. of 6-methoxy-6-methyl-5-heptan-2-ene (II). The condenser isfitted for distillation and a small quantity of benzene distilled offuntil no cloudiness is detectable in the distillate. The condenser isthen returned to a reflux position and g. of zinc slowly added to thereaction mixture at such a rate as to maintain vigorous reflux. Twohours are required to add all of the zinc. The reaction mixture is thenstirred until cool and diluted with 1 liter of water. Aqueous 5%sulfuric acid is added slowly with stirring until all of the solid whichforms on dilution with water is dissolved. The upper oii layer isseparated and the aqueous portion extracted with benzene. The oiland thebenzene extract are combined, washed with water, and then with sodiumbicarbonate solution. The benzene is removed under the vacuum of a waterpump, and the residue fractionally distilled. 224 g. (72.3%) of ethyl3-hydroxy-3,7-dimethyl-7-methoxyoctanoate (III) of boiling point 117 C.at 0.5 mm. is obtained.

(0) Preparation of Ethyl 3,7-Dimethyl-7-Methoxy-2- Octenoate (IV) In a5-liter round-bottom flask fitted with a stirrer, thermometer, andcondenser are placed 270 ml. of phosphorus oxychloride, 1 liter ofpyridine, and 1 liter of toluene, in that order. Then- 703 g. of ethyl3-hydroxy- 3,7 -dimethy1-7 -methoxyoctanoate (H1) is dropped into thestirred reaction mixture over the course of 30 minutes, causing thetemeprature to rise to 95 C. The reaction mixture is then stirred at95-100" C. for two hours with external heating. The solution is thencooled and poured into 5 liters of ice water. The oil layer is separatedand the water layer extracted with 1 liter of toluene.

The combined oillayer and toluene extract are washed.

(d). Preparation of Ethyl 3,7-Dimelhyl-7-Methoxy-Octa- 2,4-Dinoate (V)In a 5-liter round-bottom flask fitted with a stirrer, comdenser,thermometer, and nitrogen inlet tube are placed 430 g. of ethyl3,7-dimethyl-7-methoxy-2-octenoate (IV), 2.5 liters of carbontetrachloride, 200 g. of sodium bicarbonate, g. of calcium oxide, and500 g. of N-bromosuccinimide, in the order named. The reaction mixtureis heated under nitrogen until a light refluxing commences. The heatingsource is quickly removed, since the heat of reaction causes a vigorousboiling which continues for about 10 minutes. When the boiling stops,the heat ing is resumed and the reaction mixture stirred under refluxfor an additional hour. Thereafter the flask is inserted into ,a. coldwater bath and 400 ml. of quincremoved by distillation under the vacuumof a water pump. The residue is heated under a nitrogen atmosphere .for2 hours at 95100 C. The residue is allowed to cool to 60 C., and 200 ml.of pyridine is added and the heating continued for one hour at 95-110 C.The reaction mixture is cooled, poured into four liters of Water, andextracted three times, each time with 2 liters of petroleum ether(boiling point 30-60 C.). The petroleum ether extracts are combined andwashed 4 times, each time with 1 liter of 5% sulfuric acid; then twice,each time with 1 liter of water; then with 1 liter of 5% sodiumbicarbonate solution; and lastly with 1 liter of water. The organiclayer is dried over anyhdrous calcium sulfate and the solvent removedunder the vacuum of a water pump. The residue is distilled under a highvacuum oil pump. 212 g. (50%) of ethyl 3,7-dimethyl-7-methoxy-octa-2,4-dienoate (V) of boiling point 751l5 C. at0.3 mm. is obtained. An analytically pure sample is obtained bydistillation; boiling point 80 C. at 0.15 mm.

(2) Preparation of 3,7-Dimethyl-7-Meth0xy-Octa-2,4- Dien-I-Ol (VI) In a5-liter flask fitted with a stirrer, thermometer, and dropping funnelare added 2 liters of ethyl ether and 40 g. of lithium aluminum hydride.The resulting mixture is stirred for 30 minutes at room temperature, andthe mixture cooled to 10 C. Then 150 g. of ethyl 3,7-dimethyl-7-methoxy-octa-2,4-dienoate '(V) is added over a one-hourperiod. The cooling bath is removed and the reaction mixture stirred forten hours. The mixture is cooled to -10 C. and a 5% solution of sulfuricacid added drop by drop until the excess lithium aluminum hydride isdecomposed. Then a sufiicient quantity of 5% sulfuric acid is added todissolve the precipitated solid. The oil layer is removed and the waterlayer extracted with additional ether. The ether extracts and oil layerare combined, washed with Water, and dried over anhydrous calciumsulfate. The ether is removed by distillation under the vacuum of awater pump. 126 g. (100%) of crude product is obtained. The product,3,7-dimethyl- 7- methoxy-octa-2,4-dien-l-ol (VI) is fractionallydistilled; boiling point 78 C. at 0.1 mm.

(f) Preparation of 3,7-DimethyI-7-Meth0xy-Octa2,4- Dien-I-Yl T riphenylPhosphorus Bromide (VII) In a 2-liter flask provided with a stirrer anda nitrogen inlet tube are added 1 liter of methyl alcohol, 178 g. oftriphenyl phosphorus hydrobromide, and 96 g. of crude 3,7dimethyl-7-methoxy-octa-2,4,-dien-l-ol (VI) The mixture is stirred undera nitrogen atmosphere for 48 hours at room temperature. The solution isfiltered, diluted with two volumes of water, and extracted withmethylene chloride. The methylene chloride extracts are combined washedtwice with water, and concentrated under the vacuum of a water pump to athick syrup. The syrupy residue is Washed twice, each time with 500 ml.of ethyl ether. Then 1 liter of ethyl acetate is added and stirringcontinued at room temperature until most of the product is crystallized.The ethyl acetate mixture is held at C. for eight hours, after which thecrude product is filtered by suction, washed with ethyl acetate, anddried in a vacuum oven at 50 C. 105 g. (39.6%) of 3,7 dimethyl7-methoxy-octa-2,4-dien-l-yl triphenyl phosphorus bromide (VII) isobtained. After recrystall zation from methylene chloride-ethyl acetate,66 g. (25%) of pure compound is obtained; melting point 168 C.

(g) Preparation of Spirz'lloxanthin (VIII) In a 1-liter round-bottomflask fitted with a stirrer, condenser, thermometer, and nitrogen inlettube are added 600 ml. of methyl alcohol and g. of metallic sodium. Whenthe sodium is all dissolved, the contents of the flask are cooled to 20C. and 50 g. of 3,7-dimethyl- 7-methoxy-octa-2,4-dien-l-yl triphenylphosphorus bromide (VII) is added all at once and the mixture stirredfor minutes. Then 10 g. of crocetiu dialdehyde is added and the coldbath removed. The flask is placed on a hot water bath and the reactionstirred under nitrogen at reflux temperature for 4 hours. The reactionmixture is cooled for 8 hours at 0 C. and filtered by suction. Theproduct is obtained as glistening violetblack crystals. The crudeproduct yield is 18 g.; melting point 180-191 C. After fiverecrystallizations from benzene an analytically pure sample ofspirilloxanthin (VH1) (6.5 g.) is obtained; melting point in a bathpreheated to 200 C. is 217 C. (uncorrected).

EXAMPLE 2 (a) Preparation of 3-Hydroxy-7-Methoxy-3,7-Dimethylocta-1 -Yne(IX) 28 g. of metallic sodium is dissolved in 1 liter of liquid ammonia.Acetylene is bubbled into the stirred solution until the color of thesolution changes from blue to white. 158.2 g. of6-methoxy-6-methyl-heptan-2-one (H) (prepared as in Example 1) isdissolved in 150 ml. of diethyl ether and dropped into the stirredreaction mixture during the course of one hour. The stirring is thencontinued for three hours While a slow stream of acetylene is bubbledin. The acetylene introduction is then stopped and the stirringcontinued for about 15 hours. Thetammonia is distilled oif and theresidue in the reaction vessel Washed With 1 liter of 5% sulfuric acidsolution. The product is then washed with water, dried over anhydrouscalcium sulfate, and fractionally distilled to yield 157 g. of3-hydroxy-7-methoxy- 3,7-dimethyl-octa-l-yne (IX); boiling point 112 C.at 8 nun. of mercury.

(b) Preparation of 3-Hydroxy-7-methoxy-3,7-Dimethylocta-I-Ene (X) (0)Preparation of 7-Methoxy-3,7-Dimethylocta-Z-En-1- Yl TriphenylPhosphorus Bromide (XI) 186.3 g. of3-hydroxy-7-methoxy-3,7-dimethylocta-1- ene (X) and 312.2 g. oftriphenyl phosphorus hydrobromide are placed in 1860 ml. of methylalcohol and stirred under a blanket of nitrogen at room temperature for48 hours. The solution is diluted with 3 liters of water, then extracted3 times with 600 ml. of methylene chloride. The extracts are combined,washed with 2 liters of water, and concentrated under vacuum. 2 litersof ethyl acetate are added to the syrup. The mixture is stirred for 1hour and cooled for 8 hours at 0 C. A white crystalline solid,7-methoxy-3,7-dimethylocta-2-enl-yl triphenyl phosphorus bromide (X1),is filtered by suction, washed with ethyl acetate, and dried in a vacuumoven at 50 C. 384 g. (80%) of product of melting point 168-171" C. isobtained.

(d) Preparation of 1,1' Dimethoxy-Ll,2,2-Tetrahydrolycopene (XII) 1.4 g.of metallic lithium is placed in cc. of diethyl ether and reacted with17.3 g. of bromobenzene. 43.6 g. of7-methoXy-3,7-dimethytlocta-2-en-l-yl triphenyl phosphorus bromide (X1)is added. 8.0 g. of crocetin dialdehyde is added as a dry powder at sucha rate as to induce reflux.' After the addition, the reaction isrefluxed for 2 more hours, cooled to 10 C., diluted with 200 ml. of coldwater, and filtered. The precipitate is washed with water, methylalcohol, and petroleum ether. The crude product weighs 12.9 g. afterdrying; melting point 54 C. After recrystallization firom pyridine andthen 7 from benzene, 9.7 g. of 1,1-dimethoxy-1,1',2,2-tetnahydrolycopene(XII), melting point 168 C., is obtained.

(e) Preparation of Spirilloxarzthin (VIII) 20 g. of1,1'-dimethoxy-1,1,2,2'-tetrahydrolycopene (XII) is dissolved in 500 ofchloroform. 20 g. of calcium oxide, 20 g. of sodium bicarbonate, and 14g. of N-bromosuccinimide are added to the reaction mixture in theorder'given. The reaction mixture is stirred for two minutes under ablanket of nitrogen. Then 20 cc. of dimethylaniline are added and. thereaction mixture stirred under reflux for 1 hour. 10 cc. of pyridine areadded and the stirring and refluxing continued for an additional hour.The cool solution is filtered and the solid extracted with hotchloroform. The hot chloroform extract is combined with the filtrate andthe mixture concentrated by distillation until 100 cc. volume remains inthe flask. The residue is diluted with 200 'cc. of methyl alcohol andthe resulting solid refrigerated overnight. Upon filtering the methylalcohol solution, 16 g. of crude product, melting point 180 C., isobtained. After 4 recrystallizations from hot benzene, 4.0 g. (20%) ofspirilloxanthin (VIII) as a deep violet colored crystalline solidmelting at 215C. is obtained. The spirilloxanthin (VIII) is identicalwith a sample of spirilloxanthin obtained from natural sources asdetermined by mixed melting point and infrared spectra.

Variations in the process of the invention can be undertaken by thoseskilled in the art without departing from either the scope or the spiritof the invention.

This application is a division of application Serial No. 198,719, filedMay 31, 1962.

I claim:

1. A process for the preparation of spirilloxanthin comprising the stepsof 1 (a) treating 6-methyl- 5=hepten-2-one with methyl alcohol in anacidic medium to form 6rnethoxy-6- methylheptan-Z-one,

(b) treating the latter compound with sodium metal and acetylene to form3-hydroxy-7-methoxy-3,7-dimethylocta-l-yne,

(c) hydrogenating the latter compound in the presence of alead-palladium-calciurn carbonate catalyst to form3-hydroxy-7-methoxy-3,7-dimethylocta-1- ene,

(d) reacting the latter compound with triphenyl phosphorus hydrobromideto 'give 7-methoxy-3,7-dimethylocta-Z-en-l-yl triphenyl phosphorusbromide,

(e) reacting the latter compound withcrocetin dialdehyde to give1,1'-dimeth0xy-1,1',2,2'+tetral1ydrolycopene, and r (f) treating thelatter compound with N-bromosuccinimide to give spin'lloxanthin.

2. 3-hydroXy-7-methoxy-3,7-dimethylocta-l-yne.

3. 3-hydr'oxy-7-methoxy-3,7-dirnethylocta-l-ene.

4. 7-methoxy-3,7-dimethylocta-2-en 1 yl triphenyl phosphorus bromide.

5. 1,1-dimethoxy-1,1,2,2-tetrahydrolycopene.

References'Cited in the file of this patent UNITED STATES PATENTS2,671,112 Inhoifen et a1. Mar. 2, 1954 2,819,298 Isler et al. Jan. 7,1958 2,857,423 Isler et a1. Oct. 21, 1958 OTHER 7 REFERENCES Karrer etal.: Oarotenoids, 1950, pp. 295-297.

1. A PROCESS FOR THE PREPARATION OF SPIRILLOXANTHIN COMPRISING THE STEPSOF (A) TREATING 6-METHYL-5-HEPTEN-2-ONE WITHMETHYL ALCOHOL IN AN ACIDICMEDIUM TO FORM 6-METHOXY-6METHYLHEPTAN-2-ONE, (B) TREATING THE LATTERCOMPOUND WITH SODIUM METAL AND ACETYLENE TO FORM3-HYDROXY-7-METHOXY-3,7-DIMETHYLOCTA-1-YNE, (C) HYDROGENATING THE LATTERCOMPOUND IN THE PRESENCE OF A LEAD-PALLADIUM-CALCIUM CARBONATE CATALYSTTO FORM 3-HYDROXY-7-METHOXY-3,7-DIMETHYLOCTA-1ENE, (D) REACTING THELATTER COMPOUND WITH TRIPHENYL PHOSPHORUS HYDROBROMIDE TO GIVE7-METHOXY-3,7-DIMETHYLOCTA-2-EN-1-YL TRIPHENYL PHOSPHORUS BROMIDE, (E)REACTIG THE LATTER COMPOUND WITH CROCETIN DIALDEHYDE TOGIVE1,1''-DIMETHOXY-1,1'',2,2''-TETRAHYDROLYCOPENE, AND (F) TREATING THELATTER COMPOUND WITH N-BROMOSUCCINIMIDE TO GIVE SPIRILLOXANTHIN. 2.3-HYDROXY-7-METHOXY-3,7-DIMETHYLOCTA-1-YNE. 3.3-HYDROXY-7-METHOXY-3,7-DIMETHYLOCTA-1-ENE. 4.7-METHOXY-3,7-DIMETHYLOCTA-2-EN - 1 - YL TRIPHENYL PHOSPHORUS BROMIDE.5. 1,1''-DIMETHOXY-1,1'',2,2''-TETRAHYDOLYCOPENE.